Role of matrix metalloproteinase-9 in endothelial apoptosis in chronic heart failure in mice
Role of matrix metalloproteinase-9 in endothelial apoptosis in chronic heart failure in mice
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DOI：
10.1152/japplphysiol.00442.2005
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发表时间：
2005-12-01
影响因子：
3.3
通讯作者：
Tyagi, SC
中科院分区：
文献类型：
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作者：
Ovechkin, AV;Tyagi, N;Tyagi, SC
基质金属蛋白酶-9在小鼠慢性心力衰竭内皮细胞凋亡中的作用。J Appl Physiol 99：2398-2405，2005.首次发表于2005年8月4日; doi：10.1152/japplphysiol.00442.2005。氧化型细胞外基质在内皮-肌肉间的积聚是充血性心力衰竭时内皮-心肌细胞解偶联的重要危险因素。尽管心室重构伴随着基质金属蛋白酶（MMP）-9活性的增加，但MMP-9是否在慢性容量超负荷充血性心力衰竭中的内皮细胞凋亡中起作用尚不清楚。我们检验了这样一个假设，即在慢性容量超负荷中，心肌功能障碍涉及MMP-9激活、细胞外基质积聚和内皮细胞解偶联引起的内皮细胞凋亡。在对照（FVB/NJ）和MMP-9敲除（MMP-9 KO; FVB.CgMMP9（tm 1 Tvu）/ J）小鼠中建立动静脉瘘（AVF）。假手术作为对照。小鼠分组如下：野生型，n = 3（假手术对照）; MMP-9 KO，n = 3（假手术）; AVF，n = 3;和MMP-9 KO + AVF（n = 3）。AVF后8周，通过M型和多普勒超声心动图分析心脏功能，并在麻醉小鼠的左心室放置压力尖端Millar导管。通过测量caspase-3、转移酶介导的dUTP缺口末端标记（TUNEL）和通过免疫标记的CD-31来检测细胞凋亡。蛋白酶激活受体-1，连接蛋白-43，和去整合素和MMP-12（ADAM-12）的表达通过蛋白质印迹分析。用定量RT-PCR检测MMP- 2和MMP-9的表达。与对照组相比，AVF组左室舒张末压升高，-dP/dt降低。相比之下，在MMP-9 KO + AVF组中，这些变量向对照水平变化。MMP-9 KO + AVF组中AVF小鼠中EE细胞凋亡（caspase-3活化和TUNEL/ CD-31共标记）的增加被阻止。AVF中蛋白酶激活受体-1、连接蛋白-43和ADAM-12被诱导。MMP- 9基因敲除可改善上述诱导作用。结果表明，在容量超负荷心脏功能受损与EE凋亡，心脏重构，和内皮细胞解偶联在MMP-9激活的反应。
Role of matrix metalloproteinase-9 in endothelial apoptosis in chronic heart failure in mice. J Appl Physiol 99: 2398-2405, 2005. First published August 4, 2005; doi: 10.1152/japplphysiol.00442.2005.-Accumulation of oxidized extracellular matrix between endothelium and muscle is an important risk factor in the endothelium-myocytes uncoupling in congestive heart failure. Although ventricular remodeling is accompanied by increased matrix metalloproteinase (MMP)-9 activity, it is unclear whether MMP-9 plays a role in endothelial apoptosis in chronic volume overload congestive heart failure. We tested the hypothesis that, in chronic volume overload, myocardial dysfunction involves endocardial endothelial (EE) apoptosis in response to MMP-9 activation, extracellular matrix accumulation, and endotheliummyocytes uncoupling. Arteriovenous fistula (AVF) was created in control (FVB/NJ) and MMP-9 knockout (MMP- 9KO; FVB.CgMMP9(tm1Tvu)/ J) mice. Sham surgery was used as control. Mice were grouped as follows: wild type, n = 3 (sham control); MMP-9KO, n = 3 (sham); AVF, n = 3; and MMP- 9KO + AVF (n = 3). Heart function was analyzed by M-mode and Doppler echocardiography, and with a pressure-tipped Millar catheter placed in the left ventricle of anesthetized mice 8 wk after AVF. Apoptosis was detected by measuring caspase-3, transferase-mediated dUTP nick-end labeling (TUNEL), and CD-31 by immunolabeling. Protease-activated receptors-1, connexin-43, and a disintegrin and MMP-12 (ADAM-12) expression were measured by Western blot analyses. MMP- 2 and MMP-9 expression were measured by quantitative RT-PCR. Compared with control, AVF caused an increase in left ventricle end diastolic pressure and decrease in -dP/dt. In contrast, in the MMP-9KO + AVF group, these variables were changed toward control levels. Increased EE apoptosis (caspase-3 activation and TUNEL/ CD-31 colabeling) in AVF mice was prevented in the MMP-9KO + AVF group. Protease-activated receptor-1, connexin-43, and ADAM-12 were induced in AVF. MMP- 9 gene ablation ameliorated the induction. The results suggest that impaired cardiac function in volume overload is associated with EE apoptosis, cardiac remodeling, and endothelium-myocytes uncoupling in response to MMP-9 activation.